Unleashing the promise of emerging nanomaterials as a sustainable platform to mitigate antimicrobial resistance

The emergence and spread of antibiotic-resistant (AR) bacterial strains and biofilm-associated diseases have heightened concerns about exploring alternative bactericidal methods. The WHO estimates that at least 700 000 deaths yearly are attributable to antimicrobial resistance, and that number could increase to 10 million annual deaths by 2050 if appropriate measures are not taken. Therefore, the increasing threat of AR bacteria and biofilm-related infections has created an urgent demand for scientific research to identify novel antimicrobial therapies. Nanomaterials (NMs) have emerged as a promising alternative due to their unique physicochemical properties, and ongoing research holds great promise for developing effective NMs-based treatments for bacterial and viral infections. This review aims to provide an in-depth analysis of NMs based mechanisms combat bacterial infections, particularly those caused by acquired antibiotic resistance. Furthermore, this review examines NMs design features and attributes that can be optimized to enhance their efficacy as antimicrobial agents. In addition, plant-based NMs have emerged as promising alternatives to traditional antibiotics for treating multidrug-resistant bacterial infections due to their reduced toxicity compared to other NMs. The potential of plant mediated NMs for preventing AR is also discussed. Overall, this review emphasizes the importance of understanding the properties and mechanisms of NMs for the development of effective strategies against antibiotic-resistant bacteria.


Introduction
][10] However, in medicine, these values may vary up to a diameter of 200 nm. 11In the context of the medication delivery system, nanotechnology is an inventive method that can be utilized.Currently, a diverse range of natural and synthetic nanomaterials are being researched to determine whether they can be used as medication delivery systems, as the rise of drugresistant strains of disease-causing bacteria is one of human health's most signicant concerns today.More than 2 million serious diseases are caused by antibiotic-resistant bacteria globally. 12,13Recent research shows that by the year 2050, bacterial infections are expected to cause 10 million deaths annually, which will exceed the current number of deaths caused by cancer. 14Therefore, nanomaterials are used as new antimicrobial agents to treat and prevent infectious diseases.Nanomaterials can overcome antibiotic resistance mechanisms by executing various new bactericidal routes, binding and breaking bacterial membranes, and causing cytoplasmic component leakage because of their unique physio-chemical characteristics. 15Nanomaterials can target biolms and overcome recalcitrant infections due to their size (average diameter of 100 nm) and physical properties (size, shape, surface area, composition, etc.). 168][19] Thus, nanomaterialbased therapeutic approaches are promising tools for combating difficult-to-treat bacterial infections, as they can circumvent existing mechanisms affiliated with multi-drug resistance. 20So, it is worthwhile to write a review on the investigation of nanomaterials and their efficacy against antibiotic resistance.Fig. 1 demonstrates the classication of inorganic nanoparticles with antibacterial characteristics and their uses.
This article comprehensively analyzes the signicance of nanomaterials in addressing antibiotic resistance by elaborately discussing every related aspect.For different types of nanomaterials, the review discusses the techniques of interacting with microorganisms and the mechanism to ght against microbial pathogens.In addition, the physicochemical features of nanomaterials are presented in this review to study their toxicity so that health and safety can be ensured for nanomaterial usage.This review also presents economical and environmentally friendly plant-based nanomaterial extraction and the efficacy of nanomaterials as a novel drug delivery system.Furthermore, this review suggests that nanomaterials hold great promise for revolutionizing the eld of medical science through their ability to mitigate antimicrobial resistance in the human body and their potential to replace traditional chemical antibiotics.

Antibiotic resistance
3][24][25][26][27] Recently, antibiotics have been misused and overused, allowing bacteria to proliferate and increasing antimicrobial resistance (AMR). 280][31][32] Convincing data connects antibiotic consumption to the emergence of resistance.4][35] Antibiotic resistance is a natural phenomenon that arises in bacteria because of the inherent evolutionary character of bacteria, as well as bacteria's facile and quick adaption to different environments, which has both microbiological and clinical denitions. 36Microbiologically, antibiotic resistance can be dened as the existence of a genetically specied resistance mechanism that has been acquired or mutated, which classies the microorganism as resistant or vulnerable depending on using a specied break in a clinical laboratory test.In contrast, "clinical resistance" refers to antimicrobial activity correlated with an increased likelihood of unsuccessful treatment. 37n most cases, the mechanism of action of an individual antibiotic is sufficient enough to allow it to operate against only one particular target spot inside the bacterial cell.Antibiotics are known for their ability to impede bacterial cell wall formation, disrupt the cellular membranes, inhibit nucleic acid synthesis, inhibit photosynthesis, and inhibit folic acid

Nabisab Mujawar Mubarak
Dr Nabisab Mujawar Mubarak is an associate professor in the Faculty of Engineering, Universiti Teknologi Brunei, Brunei Darussalam.He is a scientic reviewer in numerous chemical engineering and nanotechnology journals.In research, Dr Mubarak has published more than 325 journal papers and 40 conference proceedings and authored 65 book chapters, and the h-index is 69.His areas of interest are carbon nanomaterial synthesis, magnetic biochar production using microwave, and wastewater treatment using advanced materials.He receives the Curtin Malaysia Most Productive Research award, Outstanding Faculty of Chemical Engineering award, Best Scientic Research Award London, and Exceptional Scientist in publication and citation by i-Proclaim, Malaysia.He also has the distinction of being listed in the top 2% of the world's most inuential scientists in chemicals and energy.The List of the Top 2% of Scientists in the World compiled and published by Stanford University is based on their international scientic publications, the number of scientic citations for research, and participation in the review and editing of scientic research.In addition, He is also awarded the Rising Star of Science Award from Research.com.Dr Mubarak is a fellow member of the Institution of Engineers Australia, a chartered professional engineer (CPEng) of The Institution of Engineers Australia, and a chartered chemical engineer of the Institute of synthesis, as illustrated in Fig. 2a. 38Several stages are required for an antibiotic to exert its antibacterial effect.It must rst penetrate bacterial cells (inux), then be stable or be triggered and collected to inhibitory amounts.Aer that, it can nd its target, engage with it, and exert antimicrobial effects.Regardless of the antibiotic's mechanism of action, chemical composition, or range of activity, changes to either of these stages lead to bacterial resistance. 39he resistance mechanism to antibacterial drugs is demonstrated in Fig. 2b.Antibacterial resistance mechanisms may be categorized as follows. 41 The development of enzymatic action that interferes with or alters the structure of antimicrobials, 3 Alterations in the permeability of the bacterial wall and the membrane surrounding the cytoplasm, 3 Changes made to the target locations of antibacterial agents, 3 Enhanced removal of an antibiotic from the cells of bacteria (bacterial efflux).
Therefore, the ability of a species of bacteria to withstand the activity of a certain antibiotic owing to inherent structural and functional characteristics can be dened as the resistance mechanism for that species of bacteria.Fig. 3a illustrates how blactam antibiotics may target a Penicillin-binding protein (PBP) to kill bacteria.In this instance, as shown in Fig. 3a, antibiotic A can enter the cell through a protein that spans the membrane, travel to its target, and then prevent the formation of peptidoglycan when it has been there.Further, Antibiotic B can also enter the cell through a porin, just like Antibiotic A. However, unlike Antibiotic A, Antibiotic B is effectively eliminated via efflux.Antibiotic C cannot get through the outer membrane, so it cannot enter the PBP, which is the target of its action.Hence, the antibiotics fail to kill the target bacteria. 42][45] Antibiotic resistance has several causes, including insufficient regulatory requirements and usage inconsistencies, a lack of awareness of best practices that lead to unnecessary or ineffectual antibiotic usage, feeding antibiotics rather than regulating infection in poultry and livestock, and internet marketing made inexpensive antibiotics readily available. 46,47The development of antibiotic resistance is a natural process that occurs in bacteria, as illustrated in Fig. 3b.However, using different antibiotics in agriculture, healthcare, and the environment is responsible for antibiotic resistance.Additional major elements that are dominant factors for antibiotic resistance include infection control guidelines, water hygiene systems, medicine quality, sanitation settings, diagnostics and therapies, and movement restrictions. 43Moreover, the transfer of genes across organisms, in addition to changes in several genes upon that microorganism's chromosome, plays a signicant part in the development of antibiotic resistance. 48here are two distinct ways in which the AMR gene may be transferred: chromosomal mutation and extrachromosomal mutation.Chromosome mutation situations arise when alterations are formed in the entire genome of bacteria, especially on the main chromosome, and it is shown through transmissions along the vertical direction, which means that it is passed down through generations of progeny.Chromosomal mutation occurs on its own and cannot be reversed.It causes alterations in the bacterial genome because of various aspects that can be physical, chemical, or both.These changes, in turn, cause changes inside the microorganism that modify the permeability and the drug objective to prevent antibiotics from affecting bacteria. 49As a result, chromosomal mutation relies on whether the pathogen's appropriateness or virulence changes.If genetically changed microorganisms dominate or develop more oen, they would begin to reproduce and cause disorders.
Furthermore, another type of antimicrobial gene transfer is extrachromosomal resistance, which can be characterized as the transmission of genetic material through plasmids, integrons, and transposons.Plasmid transmission may transmit antibiotic-resistance genes to the host cell, and drugs can alter this process by increasing transmission. 49On the contrary, transposons are sequences already present in the genome and have a high capacity for recombination and mobility.This implies that they can readily be incorporated into a bacterium's genome.It is possible to move them from one plasmid to another and from a plasmid toward a chromosome vice versa. 50,51In addition, in the event of integrons capable of encoding AMR cassettes skilled in catching and expressing integrase genes, such integrons recognize the foreign gene and integrate it at integron sites.
Moreover, bacteria can convey resistance genes to other bacteria via horizontal gene transfer, which increases the potential for this phenomenon to spread. 58In addition, bacteria that develop resistance to numerous medications are known as multi-drug resistant bacteria (MDR) and are sometimes known colloquially as "superbugs."Any bacterium has the potential to acquire multi-drug resistance (MDR).Nonetheless, a category of pathogens known as the "ESKAPE" group has a heightened propensity to do so.The "ESKAPE" group consists of the individuals listed below: 3 E means Enterococcus faecium, 3 S means Staphylococcus aureus, 3 K means Klebsiella pneumoniae, 3 A means Acinetobacter baumannii, 3 P means Pseudomonas aeruginosa, and.

Importance of nanomaterials in AMR
Nanotechnology is now essential in scientic and technical advancements in the medical and pharmaceutical elds.Nanomaterials enable altering materials' chemical and physical characteristics. 52,53In addition, the bigger the surface-volume ratio of the nanoparticles, the stronger their chemical and biological activity. 54Nanomaterials have been used for various applications, notably drug delivery, light ablation treatment, biological imaging, biosensor applications, and even as an approach to prevent antibiotic resistance, and have shown to be highly advantageous. 55,56Thus, some nanomaterials have features that make them effective against viruses, bacteria, and fungi, and they also have a high capability for combating illnesses caused by pathogens. 57,58anomaterials as antimicrobial supplements to antibiotics are very promising and receiving widespread attention because they can ll voids where medicines typically fail, such as battling mutants resistant to many drugs and biolm. 59,60anomaterials, such as organic nanoparticles and metal oxide, now used in antimicrobial therapy, exhibit various inherent and changed chemical composition characteristics.Every one of the nanoparticles, independent of the chemical makeup, can combat bacteria through multiple methods.Such a multilayer mode of action makes it far more difficult for bacteria to become resistant to the treatment.Moreover, the ability of nanomaterials to transport antibiotics to bacteria while also performing the function of a drug carrier leads to an increase in medication efficacy and a reduction in the amount of drug the body is exposed to.Drug resistance in biolms is caused by numerous factors, including a reduction in drug incorporation through the extracellular matrix (ECM), a decrease in bacterial metabolic rates, a drop in drug concentration, and the transfer of resistant genes. 61Moreover, misuse and overuse of antibiotics are responsible for eighty percent of the multi-drug resistant or extensively drug-resistant microorganisms, and infections caused by these germs are linked with signicant ill effects.Due to the proliferation of multidrug-resistant bacteria and other drug-resistant diseases, there are currently insufficient alternatives for treatment and prevention. 62Therefore, nanomaterials have the potential to meet the demand for alternate treatment alternatives for treating microbial infections, which has arisen because this need exists.
Nanotechnology is widely known as a potential therapeutic approach because of its high effectiveness and treatment response against germs.It provides a viable option for treating most bacterial illnesses, particularly those involving multi-drugresistant microorganisms. 63Furthermore, nanomaterials that can kill microorganisms in response to various internal and external stimuli while providing improved drug delivery and release are intriguing techniques. 64Nonetheless, nanomaterials may be utilized independently or with antibiotics, resulting in strong synergistic results.Table 1 demonstrates how nanomaterials may work to prevent antibiotic resistance.Furthermore, the effectiveness of nanoparticles against bacteria resistant to many drugs, their modes of action and physical characteristics, and the benets and drawbacks of using antimicrobial nanomaterials are outlined in Tables 2 and 3, respectively.

Synthesis of nanomaterials
There is a wide variety of nanoparticles that can be found widely in nature or that can be manufactured articially.Even though natural nanoparticles are present in living organisms, it is assumed that they have been present in the biosphere since the Earth was rst formed. 84As seen in Fig. 4, nanoparticles are separated into various categories according to their size and dimensions, phase composition, and the kind of material they are made of.
Furthermore, top-down and bottom-up methods are the two primary strategies that can be utilized when fabricating nanomaterials.The top-down technique includes slicing massive amounts of material into smaller, self-assembled nanoscale units. 85On the other hand, the top-down method is turned on, resulting in the term "molecular nanotechnology," which refers to assembling a specic structure by linking atoms, molecules, clusters, or clusters inside clusters, respectively, or by selforganization.Fig. 5 illustrates the synthesis of nanomaterials.

Top-down approach
The top-down approach is a complex synthesis technique used for nanoparticles.The transformation of materials in bulk into those on a nanometric scale underpins this approach. 86This method may break large quantities of material into much smaller nanoparticles.The manufacture of irregularly shaped and extraordinarily tiny particles is not a good t for top-down procedures despite these methods being easy to employ. 87onetheless, the most signicant drawback of using this strategy is its difficulty in producing particles of the appropriate size and form.
2.1.1.Mechanical milling.Ball milling is the top-down approach's mechanical technique that is simplest and most efficient.When contrasted with alternative mechanical topdown techniques, the ball milling process is typically advantageous for synthesizing various nanoparticles.Fracture of particles, plastic deformation, and cold-welding are three signicant aspects that impact the manufacturing process and assist in preserving the quality of nanomaterials. 88n addition, the ingredients are mixed in a sealed container throughout this procedure.Then, small stainless steel, Finally, the grinding process converts bulk materials to ne nanoparticles. 89,902.1.2.Laser ablation.The process of laser ablation, which uses a pulsed laser to remove molecules off the surface of a substrate to form micro and nanostructures, has a wide variety of applications in various materials. 91Laser ablation (LA) is a top-down technique that removes solid material from a substrate by putting the laser beam over the substrate.A popular LA method includes concentrating one laser beam beyond the metal object immersed in liquid.Then, the procedure generates vapor and molten metal or plasma droplets, which combine with a liquid medium to produce certain chemicals and grow as nanoparticles.

Advantages Disadvantages
Reduced likelihood of developing resistance to bacteria A high level of exposure throughout the body to medications that have been locally delivered, along with the appropriate dosages to achieve the desired therapeutic effect Longer lifespan of therapeutic effects as a result of delayed elimination Nanotoxicity affects the brain, kidneys, lungs, liver, metabolic pathways, germ cells, and other tissues and organs A wide range of therapeutic effectiveness Inability to characterize nanomaterials using methods that are not inuenced by their physical characteristics Minimal immunosuppression Chemical antimicrobials with fewer adverse effects A high level of exposure throughout the body to medications that have been locally delivered, along with the appropriate dosages to achieve the desired therapeutic effect May pass through tissue walls such as the blood-brain barrier Enhanced ease of dissolution Accumulation of nanomaterials administered intravenously in the body's cells and organs Delivery of drugs to specied areas using accumulation Release of the drug under control Furthermore, adjusting the laser settings and liquid medium may modify the nanoparticles' shape, composition, and other features.Nonetheless, as a liquid, substances such as chloroform, acetone, water, isopropyl alcohol, and ethanol, amongst others, may be used, whereas metal is most oen utilized as the solid target. 93.1.3.Sputtering.The production of nanomaterials may be accomplished by a technique known as sputtering, which involves hitting a solid plate with elements having higher energy, like gas or plasma.Sputtering is oen regarded as an efficient production process for creating thin nanomaterial lm. 94The length of the annealing period, temperature, materials used for nanoparticle fabrication, and other factors all have a role in determining the deposited layer thickness.In addition, nanoparticles' sizes and shapes are also determined by these characteristics, in addition to their shapes.Moreover, sputtering is a method in which nanomaterials are accumulated on the surface of a substrate by the ejection of particles due to the assault of high-energy ions.
For plasma-based sources to function, an electric potential must be applied between the electrodes when the environment is in the gas phase and has low pressure.Plasma is the name given to the ionized gas that results when accelerated electrons hit gas atoms; sputtering may be done using plasma ions, the most straightforward source of sputtering material. 95.1.4.Thermal evaporation.The thermal evaporation technique is considered endothermic, and the primary reaction during this process occurs when exposed to a hot temperature. 96The specic decomposition temperature is the temperature's value when reactant metal complexes break down.Furthermore, the decomposition process also involves several factors, including reaction time and pressure.The reactant being broken down creates nanoparticles that are stable and of a tiny size.Thermal evaporation is among the most oen used ways to manufacture stable nanoparticles with the capacity for self-assembly.However, evaporation at high temperatures creates thin lms on many substrates.This method is one of the several approaches used in manufacturing inorganic nanoparticles. 97In thermal evaporation, the heating of the target material is accomplished by an electrical current.In contrast, in electron-beam evaporation, the source material is heated by being bombarded by an electron beam.

Bottom-up approach
The production of nanocrystals from particles in the atomic range is the premise behind this procedure, which is another reason why it is regarded as a valuable technique.The top-down method's antithesis, the bottom-up approach, is the exact opposite of it.Through the top-down approach, the proliferation and self-assembly of molecules and atoms may result in the formation of nanomaterials with a chemical composition, structure, and size that can be precisely specied. 87.2.1.Chemical vapor deposition (CVD).When heated, bombarded by photons, or exposed to a plasma, chemical vapor deposition (CVD) occurs.This may include the dispersion of any gaseous chemical or the chemical interactions between gaseous reactants.98,99 The conventional plasma-assisted chemical vapor deposition technique.The following concisely summarizes the primary stages involved in an average CVD process.
1. Transfer of gaseous species that have been involved in a reaction to the substrate surface, 2. Species adsorption onto that surface, 3. The substrate's surface catalyzes a heterogeneous reaction on the surface, 4. The movement of the species from the surface to the growing locations, 5. Film nucleation and growth upon that substrate, 6. Desorption and transfer of gaseous reaction products.

Physical vapor deposition (PVD).
In this technique, the target functions as a cathode and is equipped with an evaporation source that vaporizes the material from a source that may be either liquid or solid.The particles of atomic size are evaporated during the heating process with an electron beam, and the collision of the newly freed particles with the gas molecules that have been injected into the chamber causes the particles to accelerate.This results in the generation of plasma, which travels via a deposition compartment and then a vacuum pump before reaching the surface, where it condenses and causes the development of a thin coating.In addition, these lms might have a thickness that ranges from a few nanometers to thousands of nanometers, depending on the circumstances. 100,1012.2.3.Chemical reduction.The chemical reduction process is the most exible method for manufacturing nanomaterials since it is so easy to use and only requires a relatively simple apparatus.Steps involved in producing gold nanoparticles using chemical reduction process are illustrated in Fig. 6.The Brust governs most chemical reduction techniques-Schiffrin two-phase process, in which chemical reduction occurs at the oil-water interface.The thiolated atoms are adsorbable in the organic phase and then stabilize in the subsequent step, which follows directly on the heels of the rst step. 102.2.4.Hydrothermal approach.Hydrothermal technique is one of the most popular nanoparticle production.104 Crystallization is a process that may occur directly from solutions during the process of material synthesis via the use of hydrothermal or solvothermal processes.This process will typically entail two parts: nucleation or crystal formation and consequent development.The phenomena that lie behind regulating size and morphology via modifying the processing parameters are the cumulative nucleation and growth rates depending on the level of supersaturation.105 Nonetheless, since water is utilized as a solvent in the hydrothermal process, this procedure is referred to as the hydrothermal process. Theprocedure is carried out within an autoclave, a kind of pressure vessel made of steel, and here, the processing conditions may be controlled by changing the temperature and/or the pressure.Furthermore, the temperature is raised above the point at which the water would boil, achieving the desired level of vapor saturation.
2.2.5.Sol-gel approach.The sol-gel method is widely regarded as a unique synthetic method for fabricating highquality nanomaterials like metal oxide nanomaterials and composites of mixed oxide. 106In addition, over the last several decades, the automotive industry has made signicant investments in the research and development of nanocomposites that are disseminated inside polymer matrices to create lightweight components.
The morphology and physical features of the materials may be precisely controlled using this process, and the sol-gel method can, in general, be broken down into ve primary stages, which have been briey explained later in this section.3 Hydrolysis: Oxygen (O 2 ) is required to form a metal oxide that may be provided when creating metal oxide nanomaterials utilizing either aqueous or organic solvents.The technique is called the aqueous sol-gel approach, while water is the reaction media.On the other hand, when an organic solvent is utilized in the process as the reaction medium, the method is referred to as the nonaqueous sol-gel.However, using either a base or an acid is helpful to hydrolyse the precursors.The following is a detailed description of the typical chemical reaction during hydrolysis.
Here, M and R have expressed metal and alkyl groups, respectively.In addition, the alkyl group is denoted by C n H 2n+1 3 Polycondensation: In this stage, neighboring molecules condense whilst the material is still liquid.This results in the elimination of alcohol and water, the development of metal oxide interconnections, and the growth of polymer lms to microscopic dimensions.The basic chemical reaction which takes place during the condensation process is specied below, Here, metal and alkyl groups have been expressed by M and X, respectively.In addition, the alkyl group is denoted by C n H 2n+1 3 Aging: The aging process causes ongoing shis and modications to the structure and characteristics of the gel.Porosity goes down, and the space between colloidal particles goes up as a result.
3 Drying: Drying is more difficult since organic constituents and water are separated to yield gel, affecting the substance's structure.Many drying methods include freeze-drying, atmospheric/thermal drying, and supercritical drying.Each method inuences the development of the gel network in a distinct way from the others.
3 Thermal decomposition: In the nal step, a thermal treatment known as calcination is carried out to remove residues as well as molecules of water from the intended sample.The temperature at which the calcination is carried out is a signicant factor in inuencing the size of pores and material density.Consequently, calcination is carried out to yield nanoparticles.
2.2.6.Green synthesis.][109][110] Nevertheless, due to problems with hazardous chemical release, high energy consumption, usage of complicated equipment, and synthesis conditions, physical and chemical procedures are progressively substituted by green synthesis approaches. 111The following may be a concise summary of the methodologies 112 and processes for the green or environmentally friendly synthesis of various nanomaterials.
To get the desired nanoparticle, rst acquire plant extract, combine the extract with a metal salt solution under a predetermined set of circumstances, decrease the size of the metal particles, and nally carry out ltering and any other necessary operations.

Physicochemical features of the nanomaterials
Antibiotics made of chemicals can be quite hazardous to their users as the composition of bulk materials primarily inuences their toxicity.However, the physicochemical properties of nanomaterials, namely size, shape, surface area, composition, etc., signicantly impact their toxicity. 113In addition, using phytochemicals in synthesizing biocompatible NPs in various concentrations makes the NP non-toxic, making it ideal for antibiotic application.Some important physicochemical properties of the nanomaterials are specied in the following subsections.

Size
Surface area and particle size are important factors in how materials interact with biological systems.Surface area increases exponentially in relation to volume with the decrease of the material size, increasing the surface reactivity of the nanomaterial both on its own and in its surrounding environment.Notably, how the system reacts, distributes, and gets rid of the materials depends on the size of the particle and surface area. 114The size of the material has been found to affect a number of biological methods, including cellular uptake, endocytosis, and the endocytic pathway's particle processing effectiveness. 115,116The capacity of nanoparticles to penetrate biological systems and alter the structure of different macromolecules, so interfering with vital biological activities, is oen responsible for their size-dependent toxicity. 117,118he size of nanoparticles also affects how they behave pharmacologically.NPs smaller than 50 nm, when administered intravenously, transverse almost all tissues quickly and can cause potentially toxic manifestations in different tissues; however, NPs larger than 50 nm, especially positively charged particles between 100 and 200 nm, are easily absorbed by RES and do not travel to other tissues.While RES protects other tissues through clearance, RES organs, including the spleen and liver, are the primary oxidative stress targets. 119umerous toxicological investigations have indicated that, in comparison to bigger particles of the same substance, smaller nanoparticles with diameters less than 100 nm have detrimental effects on respiratory health. 120,121The human respiratory system displays varying fractional depositions of inhaled particles based on size.It has been noted that all locations are deposited with ultrane particles with diameters less than 100 nm.In contrast, the tracheobronchial region is deposited with particles less than 10 nm, and the alveolar region is deposited with particles between 10 and 20 nm. 122Consequently, it has been discovered that the translocation or distribution of NPs is size-dependent, which determines their toxicological concerns.
Furthermore, the level of oral toxicity typically increases as the size of a nanoparticle decreases, which in turn effects its toxicity when swallowed.One study found that the toxicity of copper nanoparticles in the mouth rose as their size decreased.More signicantly, bigger particles remained benign even at increasing dosages, whereas smaller particles were somewhat hazardous. 123n general, biodegradable nanoparticles are probably less dangerous than nonbiodegradable ones.Semete et al. 124 examined the biodistribution and in vivo toxicity of 200-300 nm-sized (poly (D, L-lactic-co-glycolic acid)) or PLGA nanoparticles.Following a seven-day oral dosing in mice, around 40% of the PLGA particles were detected in the liver, and the remaining particles were found in the kidney and brain with no discernible damage.Particle size can impact the breakdown of the polymer matrix in addition to its size-dependent toxicity because of its capacity to produce reactive oxygen species.It is not that fewer NPs were entering the brain in this instance; rather, the surface area to volume ratio increases signicantly as particle size decreases, making it simpler for the polymer breakdown products to penetrate and be released. 125

Shape
At the nanoscale level, a nanomaterial's shape or morphology is just as signicant as its size.Nonetheless, the biological or toxicological link connected to this characteristic alone is the subject of very few studies.7][128][129] As a result, it is thought that nanomaterial shape also signicantly impacts nanobio interfaces in addition to nanoparticle size.Apart from being the primary factor in cellular absorption, a material's size is crucial in determining its surface area at a given mass dosage.The form of the nanoparticles will generally contribute signicantly to the total surface area.For example, a nanomaterial with an octagonal form will have a different surface area than a sphere of the same size.The greater catalytic activity of a nanomaterial with a bigger surface area increases its reactivity because surface atoms tend to retain unfullled high-energy bonds. 130Therefore, these nanomaterials will have a higher chance of interacting with cell biomolecules aer successfully entering the cellular environment than their micron-sized counterparts, leading to direct cellular damage and the promotion of oxidative stress 131,132 Nanoscaled bers (like carbon nanotubes) are known to provide a signicant risk of lung inammation, much like other well-known inhalable bers (like asbestos). 1335][136] Determining whether a single nanotube or a group of them has a specic hazardous impact is challenging.According to certain research, carbon nanotubes are more hazardous than silica dust or other ultra-ne carbon black.The majority of workers who were exposed to single-walled carbon nanotubes (SWCNTs) more than the permissible exposure limit (PEL) at the time had lung injuries. 137Interestingly, studies have demonstrated that carbon nanotubes (CNTs) kill specic kidney cells by preventing cell development due to a loss in cell adhesiveness. 138[141][142]

Composition and crystalline structure
Research showing similar toxicities for various nanoparticle chemistries with identical dimensions cannot be ignored despite particle size being a major factor in determining a nanoparticle's toxicity.These studies that a nanoparticle's crystalline shape and content impact its toxicity concerns.Griffitt et al. 143 found that TiO 2 of the same dimensions did not cause any toxicity issues, while nano silver and nano-copper in their soluble forms caused toxicity in all tested organisms.This highlights the role of compositions in determining the toxicities of NPs.The study used algal species, daphnids, and zebrash as models of various trophic levels. 143heir crystal structure can also inuence the toxicity of nanoparticles.In the absence of light, rutile TiO 2 NPs have been shown to cause lipid peroxidation, oxidative DNA damage, and micronuclei formation, while anatase nanoparticles with the same size and chemical makeup did not. 121Furthermore, upon interacting with water or another dispersion media, NPs can alter their structural structure.According to a report, ZnS nanoparticles reorganize their crystal structure in water, approaching the structure of a bulk ZnS piece. 144

Surface area
The surface area is a crucial factor in demonstrating toxic manifestations (epithelial-induced inammatory responses in the lungs and other organs) in rodents, according to a number of studies employing nanoparticles of various classes. 145An increase in the surface area of nanoparticles results in a dosedependent enhancement of their oxidation and DNAdamaging capabilities, which are signicantly greater than those of larger particles containing the same mass dose. 120,146][149] When utilized as drug carriers, additives, or cosmetics, a greater surface area may lead to increased reactivity with neighboring particulates, which may have adverse effects. 115The conclusion that can be drawn is that a signicant increase in biological activity results from a reduction in particle size.As a consequence of reduced volume, a greater quantity of particles can be accommodated per unit area, leading to heightened pathophysiological toxicity mechanisms such as oxidative stress, reactive oxygen species (ROS) production, mitochondrial disruption, and others. 150he characteristics of nanoparticles that induce such pronounced biological toxicity remain to be ascertained.It is hypothesized that the total number of nanoparticles per unit volume may be significant rather than the size of the particles alone, which could account for toxicity.To comprehensively understand the correlation between the surface area of a nanoparticle and its biological toxicity, a cohort of scientists examined acute lung inammation in the presence and absence of specic reactivity of various nanoparticle surface areas. 151No statistically signicant variations in toxicity were observed according to size.However, pulmonary inammation was signicantly inuenced by the total surface area.It has been unequivocally established that ultrane and ne materials with substantial surface areas can induce pulmonary toxicity, as determined by testing the effects of treatment with titanium dioxide, carbon black, and various other particles. 152,153ytotoxicity may also be signicantly inuenced by particle surface reactivity, dened as the ease with which individual particles aggregate.[156]

Surface charge
In addition to the dimensions and morphology of the nanoparticles, their antibacterial efficacy and cytocompatibility are signicantly inuenced by their surface charge. 157Positive charge nanoparticles are encouraged to adhere to bacterial internal components, including DNA, which possess negative charge in addition to their negatively charged surfaces.The binding efficiency of positively charged nanoparticles to bacterial cell surfaces is enhanced compared to negatively charged nanoparticles, owing to an electrostatic phenomenon. 158How nanoparticle surfaces form in situ complexes with bacterial cell surfaces remains a matter of debate, which impedes the development of a comprehensive comprehension of the relationship between binding and charge efficacy. 159The process of ion exchange facilitated by cationic nanoparticle deposition at sites of infection may enable access to bacterial cells. 160Several studies have demonstrated that cationic liposomes encapsulate antibiotics more effectively, facilitating the internalization of the drugs to the biolm at reduced concentrations. 161On the other hand, some studies found that charge-negative nanoparticles could remarkably bind to bacteria, indicating that electrostatic repulsion is not  the dominant force at work when it comes to nanoparticles' high surface energy. 162Mixed-charged nanoparticles, which disrupt bacterial cell walls via electrostatic and noncovalent attachment, have recently garnered considerable attention. 163

Concentration
Concentration is a crucial last factor to consider while assessing nanomaterials' toxicity.According to research by Santos et al., 164 thermally carbonized and hydrocarbonized porous silicon particles were harmful to cells at concentrations of [mt]2 mg mL −1 ; for porous silicon particulates that are thermally oxidized, the nontoxic threshold value was 4 mg mL −1 .Research on the toxicity of several nanoparticle types (TiO 2 , MoO 3 , Al, and Fe 3 O 4 ) in vitro was done by Hussain et al. 165 in BRL 3A rat liver cells.They c that mitochondrial activity will drastically deteriorate when subjected to Ag nanoparticles at concentrations of 5-50 mg mL −1 .When Ag nanoparticle concentrations reached 100-250 mg mL −1 , cell LDH leakage increased.Similar ndings were made by Usenko et al., 166 who used embryonic zebrash to test the toxicity of carbon fullerene and found that exposure to 200 mg mL −1 C60 and C70 signicantly increased the number of abnormalities.Thus, it is evident that nanomaterials' toxicity depends on their physicochemical properties.The comparison of the toxicity between traditional antibiotics and nanomaterials is specied in Table 4.
Mohamed et al. 169 conducted an experiment on rats to determine the level of toxicity between nanobiotics and conventional antibiotics.Aer 24 hours exposure to various concentrations of linezolid, doxycycline, and clindamycin nanobiotics, the percentage of viable rat hepatocytes relative to the control group in comparison to their conventional antibiotic counterparts is depicted in Fig. 7.The values presented are the means (± standard deviation) of three separate experiments.
The results of the cell viability experiment, as shown in Fig. 7, conrmed that hepatocytes treated with nanobiotic formulations had greater percentages of live cells than those treated with traditional antibiotics, indicating that nanobiotics are more cytocompatible and less toxic.

Interaction of nanomaterials with microorganisms and antibacterial potential
Several mechanisms determine interactions between nanomaterials and bacteria, including electrostatic attraction, hydrophobic contact, the interaction between receptors and ligands, and van der Waals forces.Studying fundamental interactions between nanoparticles and bacteria gives vital knowledge for formulating innovative antimicrobial drugs.Nanoparticles have six primary antibacterial actions, which are as follows: [170][171][172] (i) Direct contact with the cell wall and membrane of the bacterial organism, (ii) Cell membrane penetration, (iii) Production of reactive oxygen species (ROS), (iv) Protein synthesis inhibition and damage of DNA, (v) Damage to the pathway of metabolism and (vi) Inhibition of biolm formation.
Fig. 8 demonstrates the mechanism of nanomaterial antibacterial action mentioned above.In addition, nanomaterials can potentially be of tremendous value in the ght against MDR bacteria as they do not exhibit the same modes of action as conventional antibiotics. 173s can be seen in Fig. 8, bacteria have developed several defense mechanisms that allow them to avoid being killed by antibiotics.This is how bacteria have survived the widespread use of antibiotics.Biolm formation independently confers antibiotic resistance, which is a distinct phenomenon from the genetic acquisition of resistance. 175Bacteria can self-colonize, which Review RSC Advances results in the formation of biolms.Infections caused by biolms are difficult to cure because the extracellular matrix formed by the bacteria forms a microenvironment inside the host.This makes it possible for bacteria to elude the immune system's defenses and dramatically increases their resistance to conventional antibiotic treatments. 176The creation of biolm therapies relies heavily on Antimicrobials can't penetrate the bacterial cell membrane since they have been modied through time to behave as a physical barrier.The bacterial cell wall composition is the primary factor determining whether bacteria are categorized as Gram-negative or Gram-positive.Teichoic acids are found in the cell walls of Gram-positive bacteria, whereas lipopolysaccharide is in the outer membranes of Gram-negative bacteria.Both types of bacteria include phosphate groups, which cause the surfaces of the bacteria to be negatively charged.This extremely polar environment restricts hydrophobic antimicrobials' membrane penetration and bacterial action.Gram-negative bacteria are distinguished by the presence of an additional layer that may be found between the plasma membrane and the outermost layer.However, this layer is far thinner compared to the outer layer of Gram-positive bacteria.As a result, it is more vulnerable to penetration by antimicrobial nanomaterials, which may eventually lead to the cell's demise 177,178 (Fig. 9).
The fundamental method via which nanoparticles might harm bacterium is oxidative stress induced by reactive oxygen species (ROS) since bacteria can keep a balance throughout the formation of ROS under normal circumstances.Nonetheless, this equilibrium is inuenced when it touches some nanoparticles.This results in excessive ROS, eventually changing the state of oxide-reduction molecules, favoring the oxidation of biological constituents.Once the nanoparticles have broken through the cell wall, they tend to release ions and produce ROS via a process known as adsorption, which is a kind of diffusion. 179Moreover, DNA damage and impairment of protein synthesis are other processes linked to metal nanoparticles in most studies.These typically induce a breakdown in enzymes, ribosomal component proteins, and other proteins generated in bacterial cell membranes, as well as compaction, degradation, and bacterial DNA fragmentation, reducing the physiological function of genes. 180However, it has been revealed that when nanostructures enter the bacterial cell, there are alterations in the metabolism of the bacterium, which in turn causes cell damage to the membrane, which in turn induces oxidative stress, which ultimately leads to the killing of the bacterium. 181inally, nanoparticles interacting with bacterial biolms Review RSC Advances connect with EPS, allowing any chemical molecule to reach the bacterium and destroy the cell. 38n contrast to antibiotics, nanomaterials may have more contact with cells owing to a larger volume-to-surface ratio, making nanoparticles adaptable for use as strategic active ingredients.Nanomaterials on their own oen contain complicated processes that function concurrently to prevent the generation of genetic alterations in bacteria and to restrict their development. 182n addition, nanoparticles as antibiotic adjuvants also work as protectors, meaning they may boost serum concentrations of the medications and protect against the enzyme system of the target.On the contrary, antibiotics lose some of their effectiveness over time, and the body of a human can only absorb half of the medication before the other half is ushed out during urination, reducing the antibiotic's effectiveness.Techniques for interacting nanoparticles with microorganisms are outlined in Table 5.Further, the investigations listed in Table 6, which various researchers carried out, showed that using metal nanoparticles functionalized with antibiotics resulted in a more potent suppression of multi-resistant bacteria, demonstrating the antibacterial potential of several nanomaterials.

Application of nanomaterials in medical science
Nanotechnology is extensively employed in contemporary biomedicine, particularly in the eld of drug delivery.A significant obstacle in attaining the intended bioavailability and suitable levels of drug efficacy is the considerable difficulty posed by the near-insolubility of an estimated 60% of all drug entities in development. 214The advancement of nanotechnology has facilitated not only the encapsulation of drugs to increase their solubility but also their permeation through membranes, which results in extended circulation durations and improved overall efficiency.Targeted therapeutics have emerged with expanding knowledge in this domain and implementing a multidisciplinary strategy.These enable the desired drug to selectively target a specic site of action within the body.As a result, numerous toxic, immobile, and impermeable substances have been permitted to progress to clinical trials as prospective treatments. 215anomaterials are used in medical diagnoses like imaging diagnosis, laboratory diagnosis, genetic disease diagnosis, and tumor early diagnosis.They are also used in the synthesis of medical instruments-for instance, nanoprobes, nanorobots, handheld disease diagnosis instruments, and nanosensors.Most importantly, nanomaterials are becoming very common in tissue engineering to fabricate nanobones.Nanomaterials are also utilized as nanoscale red blood cell substitutes.In the drug industry, applications of nanomaterials in therapeutic drugs include antibacterial nano-drugs, antiviral nano-drugs, antitumor nano-drugs, analgesic and anti-inammatory nano-drugs, encapsulating hormone drugs, nanometer polypeptide, and protein drugs.Furthermore, nanomaterials are very efficient and widely used in nanogene medicine, gene therapy of cancer, nano vaccines, and as radiosensitizers in radiation therapy. 216nomaterials are being extensively studied in medical science for drug delivery due to the mutual penetration of nanoscience and current technology. 217Drug delivery aims to maximize bioavailability at certain sites in the body and over an extended period.Molecular targeting using nanoengineered carriers may be one way to do this. 218The following features of medications transported by nanocarriers are different from those of conventional pharmaceuticals.
• Nanoscale carriers can encapsulate hydrophobic drugs due to their substantial surface area.This results in enhanced drug solubility and diminished reliance on co-solvents, customary in conventional drug formulations, to mitigate adverse effects. 219 Through the endothelial cell gap, nano-drug carriers can traverse into the lesions, in addition to traversing the blood circulation into the capillaries.Phosphocytosis enables the cellular uptake of drugs transported by nanodrug carriers.Signicant improvements will be observed in the bioavailability of the drugs. 220 Tailored nanodrug carriers, including magnetic NPs and drug-loading NPs modied with folic acid, facilitate the efficient delivery of drugs to the intended tissue.This reduces the required dosage for drug administration and mitigates the associated adverse effects. 221][224] • Nanomaterial drug carriers can reduce the frequency of drug administration by enhancing the duration and efficacy of drug concentration in the blood and extending the half-life of drug elimination. 225 Nanomaterial drugs have the capability to traverse various cellular biological membrane barriers, including those between the blood and eyes, brain, and blood vessels.[228]

Advantages of NMs based antimicrobial over chemical antibiotics
Antibiotics are substances that, when administered correctly, inhibit the development of pathogens, combat certain diseases, and potentially preserve lives.These are the fundamental pharmacological options for biolm and planktonic infections. 229On the other hand, Nano antibiotics (nAbts) refer to antibiotic molecules in their puried form that have undergone synthetic growth to achieve a minimum average diameter of 100 nm in a single dimension, or engineered nanoparticles (NPs) that contain the antibiotic molecules.
Conventional or chemical antibiotics oen induce bacterial mortality through various mechanisms, including inhibition of protein synthesis, disruption of cell wall structural components, and inhibition of proton transport across the cell membrane. 230In response to stimuli, multifunctional antimicrobials encapsulated in NPs interact with the bacterial cell wall surfaces and membranes, thereby enhancing drug distribution to target sites and passage through membranes.Moreover, nAbts possess a controlled, target-specic release mechanism that enables their administration in a single dose in contrast to the majority of conventional antibiotics, which necessitate the administration of numerous dosages for systematic release. 231Likewise, when comparing chemical or traditional antibiotics to nanoparticlebased delivery systems, the dosage of antibiotics administered through such systems offers several additional advantages.These include reduced dosage and frequency requirements, sustained drug release that enhances targeted drug delivery, and drug efficiency to a particular site within the bacterial cell. 231,232nlike molecular substances, nanoparticles (NPs) possess a highly capacious contact area due to their distinctive surface area and high surface-to-volume ratio.Antibiotics are delivered to the intended sites of action, while the NPs activate an array of antibacterial defenses concurrently when they are combined with antibiotics.For the treatment of multi-drug resistant (MDR) strains, NPs, therefore, offer a greater number of functionalities than the effects of a single medication or a combination of multiple therapies. 76,233The benets and intensity of antimicrobial nanoparticles compared to chemical antibiotics are discussed in Tables 7 and 8, respectively.
A side effect is dened as an unintended consequence of antibacterial compounds that is neither suboptimal nor complements their intended function.Controllability pertains to the capacity of antibacterial agents to undergo engineering processes that produce desired biological responses within the body, including but not limited to protracted blood circulation and targeted biodistributions.
Antibiotic discovery and development in the twentieth century had a substantial impact on the battle against bacterial illnesses.In contrast, bacterial antibiotic resistance represents a far more signicant problem due to the constant evolution of bacterial genomes.In order to address this challenge, numerous domains are implementing nanotechnology, including targeted antibiotic delivery and antibacterial vaccination facilitated by nanoparticles. 238According to several reports, zinc oxide, silver, and gold nanoparticles work well as antimicrobial agents against bacteria that are resistant to multiple drugs, including Escherichia coli, MRSA, Pseudomonas, and Klebsiella.Nanoparticles present several benets when employed as transport for antimicrobial agents.These include enhanced bioavailability, decreased probability of drug toxicity, and the ability to accumulate subtherapeutic drugs.Furthermore, an additional promising approach that may yield positive results is nanophotothermal therapy, which makes use of fullerene and functionalized antibodies as nanostructures. 239However, despite its ability to aid in the battle against antibiotic-resistant bacteria, nanopreparations may be hazardous to the environment.Even though they have antibacterial action and other promising applications, it is important to consider any possible harm to the environment.In addition, the environmental and biological risks posed by nanoparticles vary.Their large surface area, compact size, and unique physicochemical properties allow them to interact with both biological matter and the surrounding environment.Ecological processes, ecosystems, and species may suffer as a result of these interactions.Therefore, in order to address the potential ecotoxicity of nano preparations, comprehensive risk assessment processes should be devised.This involves evaluating the potential risks to the environment and public health, in addition to the exposure routes and hazards.It is essential to establish regulatory frameworks that ensure the ethical and sustainable development, use, and disposal of nanopreparations. 240,2413][244] Considering all of the useful uses for nanoparticles, scientists are now investigating possible drug delivery methods that might use nanoparticles to maximize the therapeutic usage of antibiotics while minimizing their negative effects.Table 9 shows instances of how applied nanomaterials are being used to ght drug resistance.
The high therapeutic index and effectiveness of nanotechnology against microorganisms make it a potential therapeutic approach. 63For the majority of bacterial infections, particularly those involving pathogens resistant to several drugs, nanoparticles provide a promising substitute.Antibiotics and nanoparticles work very well together when paired, either alone or in combination.Promising approaches include nanomaterials that may support improved medication delivery and release while also responding to a variety of endogenous and external stimuli to kill microorganisms. 64,253

Safety and efficacy of nanomaterials
Antimicrobial nanomaterials have recently been the subject of much-increased research with the goal of treating biolm infections and multidrug-resistant (MDR) planktonic bacteria.The creation of appropriate in vivo and in vitro models that accurately reect the safety and efficacy of nanoparticles is necessary to provide clinical feasibility for their use. 254Antimicrobial Ag NPs make up the majority of formulations that are presently in clinical trials.Although NPs can potentially treat bacterial infections, a number of obstacles need to be overcome before they can be effectively applied in the clinic.These include further research into how NPs interact with different cells, tissues, and organs, the best dosage, appropriate delivery methods, and toxicity following both acute and extended exposure. 255,256Despite the fact that nanoparticles (NPs) have demonstrated promise in antimicrobial treatment, there are several drawbacks to using them.Toxicity: Certain NP forms may be harmful to cells, resulting in unfavorable side effects.NP toxicity can be impacted by surface charge, shape, and size. 255ifficulty in targeting particular cells: It limits the efficiency of NPs and raises the possibility of adverse effects.It can be difficult to target certain cells or tissues in the body.
Ineffective against some bacteria: Treatment may be more difficult when using NPs since they may be less efficient against certain bacterial species or bacterial biolms. 257otential for resistance: It is feared that similar to how bacteria become resistant to antibiotics, they may also become resistant to NPs.This may restrict the long-term efficacy of antibacterial medicines based on NPs. 255,258egulatory obstacles: As NPs are a relatively new eld of study in antimicrobial treatment, getting regulatory permission for their usage may be difficult.Their usage and availability in therapeutic settings may be restricted as a result. 259ost: Because NPs can be costly to create and produce, some patients may not be able to obtain or afford them.
However, in contrast to conventional antibiotics, the distinctive physical structure of NPs confers a number of substantial advantages.The advantageous effects and negative consequences of nanomaterials in therapeutic usage are spec-ied in Table 10.

Plant-based nanomaterials as a viable substitute for multidrugresistant bacterial infections
Plant-based nanoparticles for treating MDR-bacterial infections are produced by the secondary metabolism of plant tissues, such as roots, owers, bark, stems, shoots, seeds, and leaves.These secondary metabolisms react very quickly when exposed to external stimuli and other signals. 260The biosynthesis of metal nanoparticles (NPs) aroused interest in the clarication and characterization of the processes of metal ion absorption and bioreduction by plants due to the great stability and quick pace of biosynthesis of plant-based NPs.Numerous studies have demonstrated that plant extracts contain a wide range of secondary metabolites, including coenzymes that function as reducing and stabilizing agents in the bioreduction reaction that produces metallic NPs, as well as phenolic compounds, alkaloids, avonoids, tannins, saponins, steroids, terpenoids, etc.These metabolites can act as potential precursors for the safe synthesis of nanomaterials.
In contrast to AgNPs used alone, Jyoti et al. (2016) demonstrate that 'green' AgNPs, combined with conventional antibiotics, have an advantageous synergistic effect. 261The study revealed that the aqueous extract of Urtica dioica (Urticaceae) leaves capped AgNPs, and amoxicillin had a synergistic enhancing role.The maximum impact was reported for amoxicillin with easy bottom-up 'green' generated AgNPs against Serratia marcescens, with a 17.8-fold increase in the inhibitory zone. 261Antibiotics and plant-based nanoparticles (NPs) have been found to interact in additional ways, including AgNPs and Zea mays extract (Poaceae) from corn leaf detritus.AgNPs and Typha angustifolia leaf extract (Typhaceae), combined with gentamicin, cefotaxime, and meropenem, demonstrated efficacy against E. coli and Klebsiella.Kanamycin and rifampicin were efficacious against ve strains of bacteria. 262hus, antibiotics and synthetic green metallic nanoparticles seem to work well together to reduce toxicity and resistance in multidrug-resistant bacterial infections. 263The green synthesis of metal NPs is shown in Fig. 10.

Extraction of plant extract
Extracts from a wide variety of plant species have already been applied to the biosynthesis of NPs, with success, including cobalt, copper, silver, gold, palladium, platinum, zinc oxide, and magnetite. 260Plant extracts are made by drying and treating plant parts such as leaves, roots, owers, fruits, peel, seeds, bark, and stems with methanol. 264Plant extracts contain various phytochemicals such as proteins, avonoids, phenols, carbohydrates, amino acids, terpenoids, saponins, tannins, steroids, anthocyanin, alkaloids, and coumarins, which carry out the reduction, capping, and stabilizing processes on the metals added to the extract, resulting in the synthesis of green metal NPs. 265lants such as Aspalathus linearis, Caesalpinia spinosa, Centella asiatic, Cinnamomum cassia, Citrus unshiu, Coffea canephora, Myrica Esculenta, and Vitis vinifera produce aspalathin, tannic acid, kaempferol, cinnamic acid, narirutin, chlorogenic acid, myricetin, and resveratrol phytochemical compounds respectively for the synthesis of AuNPs and Centella asiatic, Cinnamomum zeylanicum, Cinnamomum zeylanicumverum, Citrus paradise, Curcuma longa, Cyclopia intermedia, Cynomorium coccineum, Eucalyptus globus, Memecylon umbellatum, Mentha pulegium, Stachys tuberifera, Thymus vulgaris, and Vitis vinifera, which further produce quercetin, cinnamaldehyde, eugenol, naringin, curcumin, hesperidin, gallic acid, caffeic acid, 4 N-methyl benzoic acid, diosmin, stachyose, thymol, and resveratrol compounds respectively for synthesis of Ag NPs.Moreover, Aspalathin and ellagic acid extracted from Aspalathus linearis and Rubus idaeus are used to produce RhNP and ZnNP, respectively. 266n addition to plant extracts, live plants can synthesize metal nanoparticles.When silver is present in the substrate, some plants, such as Brassica juncea (Mustard greens), Medicago sativa (Alfalfa), and Helianthus annuus (Sunower), can accumulate a signicant amount of silver.In addition, Ni, Co, Zn, and Cu NPs have been synthesized in living plants.The bioaccumulated metals are stored in various parts of the plants, and metal NPs are obtained directly from these parts through chemical processes. 2671.Types of phytochemicals in the extract and their role Proteins, avonoids, phenols, carbohydrates, amino acids, terpenoids, saponins, tannins, steroids, anthocyanin, alkaloids, and coumarins are some of the most common phytochemicals used in the production of metal NPs.These phytochemicals reduce, cap, and stabilize metal nanoparticles (NPs).For example, polysaccharides, vitamins, amino acids, proteins, phenolics, saponins, alkaloids, and/or terpenes are used to reduce and stabilize the Ag ions in AgNPs.268 In producing gold NPs, various chemical moieties in biogenic complexes act as reducing agents, reducing gold metal ions and forming nanoparticles.According to some studies, biomolecules such as avonoids, phenols, proteins, and others are essential in lowering metal ions and topping gold nanoparticles in plant extracts.269 Aromatic amines can also produce Pt and Pd-based NPs via domino and tandem reactions.270 Metal NPs (such as Au, Ag, Cu, Pd, Se, and Pt NPs) are produced by amino acids such as -amylase, urease, and protease by binding metal ions to exposed free cysteine and reducing the metal ion.The reduced metal ions are then capped by the formation of disulde bonds with the help of the lysosome enzyme.Polyphenols such as avonoids, phenolic acid, terpenoids, and proteins reduce and stabilize metal NPs via a similar mechanism 271 -the metal-chelating ability and, thus, the metalreducing ability of phenolic acid's nucleophilic aromatic rings.During bioreduction, the -OH groups of avonoids (quercetin and myricetin) and terpenoids combine with metal ions and are oxidized to carbonyl groups.Proteins aid in stabilising metal NPs during the nucleation process, and capping the nucleated metal NPs aids in their stability.272

Various parameters of extract affecting morphology and size of particles
Factors inuencing the preparation and properties of plantbased metal NPs include the type of plant extract used, its concentration, the pH of the medium, the concentration of the metal salt, contact time, and temperature.These variables have been shown to inuence the rate, properties, and quantity of prepared nanoparticles.Makarov et al. (2014) observed that the size and shape of the NPs are highly dependent on their location.The most common plant extract parameters inuencing particle morphology, shape, and size are described below. 268 Plant extract type and concentration: The concentration of plant biomass/extract oen determines the efficiency of nanoparticle synthesis.Several researchers discovered that increasing the biomass dosage boosts nanoparticle production and changes the shape of nanoparticles. 273 Chandran et al. (2006) used Aloe vera leaf extract to modulate the shape and size of the synthesized Au nanoparticles. 274Most of the Au nanoparticles were triangular and ranged in size from 50 to 350 nm, depending on the extract used.Adding small amounts of the extract to the HAuCl 4 solution resulted in the formation of larger nanogold triangles.Furthermore, as the amount of extract increased, the ratio of nanotriangles to spherical nanoparticles decreased. 273 pH: A solution's pH inuences nanoparticle synthesis using green technology methods.According to the researchers, the solution medium's pH affects the synthesised nanoparticle's size and texture.This is caused by the formation of nucleation centers, which increases as pH increases. 273As a result, the size of nanoparticles can be controlled by adjusting the pH of the solution media.Soni and Prakash (2011) demonstrated the effect of pH on the shape and size of the synthesized silver nanoparticle. 275 Temperature: In most cases, using green technology to synthesize nanoparticles requires temperatures less than 100 °C or ambient temperature.The nature and size of the nanoparticle formed are determined by the temperature of the reaction medium. 276 Pressure: The shape and size of the synthesized nanoparticles are affected by the pressure applied to the reaction medium.The rate of metal ion reduction using biological agents was discovered to be much faster at ambient pressure conditions. 277 Time: The time and the incubated reaction medium signicantly impact the quality and type of nanoparticles synthesized using green technology. 278Variations in time can occur in various ways, including particle aggregation because of long-term storage; particles may shrink or grow due to longterm storage; they may have a shelf life, and so on, all of which affect their potential.
3 Environment: The surrounding environment signicantly impacts the nature of the synthesized nanoparticles.In many environments, a single nanoparticle quickly transforms into core-shell nanoparticles by absorbing materials or reacting with other environmental materials via oxidation or corrosion. 279In a biological system, the nanoparticles form a coating that thickens and expands them.Furthermore, the environment inuences the physical structure and chemistry of the synthesized nanoparticles.There are a few examples of how the environment affects the nature of synthesized nanoparticles.When the environment of the zinc sulde nanoparticles was changed from wet to dry, the crystalline nature of the nanoparticles changed immediately.Similarly, the chemical nature of cerium nitrate nanoparticles changes depending on the amount of peroxide present in the solution in which they are suspended.
3 Proximity: When individual or isolated nanoparticles meet or near the surface of another nanoparticle, their properties are altered in most cases.This changing behavior of nanoparticles can be used to create more tailored nanoparticles.The proximity effect of nanoparticles has many implications, including particle charging, substrate interactions, and magnetic properties of the nanoparticles. 280 Other considerations: Secondary metabolites are abundant in various living systems, including plants, and act as reducing and stabilizing agents in the synthesis of nanoparticles.However, the composition of these metabolites varies depending on the type of plant, plant part, and extraction method used.The concentration of metal ions also signicantly impacts the effectiveness of various phytochemicals, which in turn determines the morphology and size of the metal NPs produced.

Challenges and future perspective
There is a growing interest in improving drug delivery for disease resolution.As a result, candidates such as biogenic metal-based nanoparticles with improved biodistribution and pharmacokinetics have a one-of-a-kind opportunity. 295Metallic nanoparticles inspired by nature represent a new generation of innovative nanomedicines that mimic natural circulatory cells.These materials have been discovered to have the ability to increase blood circulation time and improve drug distribution to cells and tissues. 223The role of nanotechnology in the precise treatment of diseases, which oen has less life-threatening side effects, has the potential to contribute to a positive shi in clinical practice toward life-saving approaches.However, their immunogenicity, scale-up, and characterization remain significant challenges during clinical trials. 296Aside from scaling-up issues, government regulations and overall cost-effectiveness compared to currently available chemotherapies are substantial barriers to the success of nanomedicines.The oencomplex architectural design of many biogenic metal NPs may also make it challenging to perform reproducible, safe, and sufficient sample preparations.One of the most difficult challenges has been reproducibility, as minor changes in NPs size, shape, and/or surface chemistry can dramatically affect their stability, interaction with biological media, and biodistribution. 265As a result, reproducible nanoparticles require reliable and standardized methodologies.Furthermore, for these materials to be excellent biological tools, the gap between the laboratory, where innovative materials are designed, and the industrial replication of the process, where reproducible preparation and manufacturing processes are carried out, must be narrowed.There is an exciting future for NPs in combining them to act as 'nanomachines': their mode of interaction would have a non-linear dependence on changed parameters such as temperature or pH.This approach appears to be working, and the future of nanotechnology is getting closer; however, its potential threats must be considered, and the effects of new procedures must be carefully examined before they are implemented.For example, the toxicity of nanoparticles (NPs) is critically discussed to identify potential issues before they are widely used in medicine.On the other hand, synthesis mediated by plant extracts is said to be environmentally friendly.One of the most notable trends in the synthesis of metallic NPs from plant extracts could be a benecial strategy for characterizing the mode of action of NPs. 267It is a controlled synthesis that can be easily transferred to a large scale and ensures environmental safety while reducing the process's environmental impact.Taken as a whole, the use of plant-based NPs has demonstrated a variety of benets and applications in medicine and the pharmaceutical industry.More specically, studies show that NPs can exert antimicrobial properties alone or in combination with antibiotics, reducing the current problem of acquired resistance caused by antibiotic overuse or misuse.Given this potential application, future research should concentrate on two areas: assessing the safety aspects of using plant-based NPs (toxicity to human health and environmental safety) and reducing the environmental impact of their synthesis.More detailed development of synthesis procedures is required, as is research into the action mechanisms that mediate the antibacterial effect of NPs to make plant-based NPs a viable strategy capable of meeting society's demand for an effective solution to antibiotic resistance.

Summary
This review meticulously summarized the various emerging nanomaterial platforms to mitigate antimicrobial resistance.The review includes the synthesis of nanomaterials the extraction of cost-effective and eco-friendly plant-based nanomaterials as a viable alternative to combat multidrug-resistant bacterial infections.In addition, this study examines the toxicity of nanomaterials by thoroughly investigating the physicochemical properties of these materials, intending to utilize them as a feasible alternative to chemical antibiotics.The mechanism of action of nanomaterial on pathogenic organisms is also elaborately presented in this review, along with the techniques of different nanomaterials to ght against microbial pathogens.Moreover, applications of nanomaterials in medical science, novel drug delivery systems for nanomaterials, and the advantages of antimicrobial nanomaterials over chemical antibiotics are also covered in this review.Therefore, this review could be valuable in establishing innovative and effective therapeutic approaches for antimicrobial therapy.It is evident that nanomaterials have the potential to bring about a revolutionary change in medical science by mitigating antimicrobial resistance in the human body, and they can serve as a substitute for conventional chemical antibiotics.Plant-based nanomaterials can be crucial in reducing toxicity in the human body and ensuring human safety, offering both environmental friendliness and economic benets.In addition, nanomaterials have the potential to have a signicant impact on novel drug delivery methods and therapeutic applications.

Fig. 2
Fig. 2 (a) Antibiotic mechanism of action, and (b) antibiotic resistance mechanisms in bacteria (Reprinted with permission from, 40 An Open Access article distributed under the terms of the Creative Commons Attribution License).

Fig. 4
Fig. 4 Representative schematic flowchart of the nanomaterial's classification (Reprinted from 84 with permission from Elsevier).

Fig. 5
Fig. 5 Schematic drawing related to the synthesis of nanomaterials (NPs) via top-down and bottom-up approaches (Reprinted from 84 with permission from Elsevier).

Fig. 6
Fig. 6 Stages involved in producing gold nanoparticles by chemical reduction (Reprinted from ref. 103 with permission from Elsevier).

Fig. 8
Fig. 8 Nanomaterial action mechanisms in bacterial cells (Reprinted with permission from ref. 174, An open access article distributed under the terms of the Creative Commons Attribution License).

Fig. 10
Fig. 10 Different parts of the plant are used for extract and mechanism of formation of nanoparticles. 281

9. 3 .
Literature reports on different parts of plants used as an extract for the synthesis of NPsAgNPs and AuNPs are the most investigated plant-based NPs, primarily associated with developing potent antimicrobial NPs.

Table 1
Nanomaterials for the elimination of antibiotic resistance

Table 2
Nanomaterial efficacy against multidrug-resistant bacteria, as well as modes of action and physical properties

Table 6
Resistance against microbial pathogens using nanomaterials

Table 7
Difference between nanoantibiotics and chemical antibiotics

Table 9
Nanomaterial against the emergence of antibiotic resistance

Table 10
Advantages and disadvantages of nanomaterials in therapeutic usage

Table 11
Different parts of various plants used in the synthesis of metal nanoparticles